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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI204613

Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma

Katrine N. Madsen,1 Soki Kashima,1 Hanna Soulati,1 Lena Wirth,1 Katsuhiro Ito,1 Zachary A. Yochum,1 Vivien Moritz,1 Julia Walker,1 Marc Machaalani,2 Fady Ghali,3 Patrick Kenney,3 Adebowale Adeniran,4 Michael Hurwitz,5 Toni K. Choueiri,2 and David A. Braun1

1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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1Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, United States of America

2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

3Department of Urology, Yale School of Medicine, New Haven, United States of America

4Department of Pathology, Yale School of Medicine, New Haven, United States of America

5Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, United States of America

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Published October 6, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI204613.
Copyright © 2026, Madsen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 6, 2026 - Version history
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Abstract

Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2α inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2α inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of EPAS1 (encoding HIF-2α) perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2α inhibition in vitro and in peripheral blood from patients receiving HIF-2α inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2α inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2α–targeted therapy in ccRCC.

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Version history
  • Version 1 (October 6, 2026): In-Press Preview
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